- Title Information
- Title
- The Neural Effect of Chitinase-3-like Protein 1 (CHI3L1/YKL-40) in Neuroinflammation & Alzheimer’s Disease
- Type of Resource (primo)
- dissertations
- Name:
Personal
- Name Part
- Connolly, Kevin
- Role
- Role Term:
Text
- creator
- Name:
Personal
- Name Part
- Huang, Alvin
- Role
- Role Term:
Text
- Advisor
- Name:
Personal
- Name Part
- Sedivy, John
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Lee, Chun
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Webb, Ashley
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Musiek, Erik
- Role
- Role Term:
Text
- Reader
- Name:
Corporate
- Name Part
- Brown University. Department of Molecular Biology, Cell Biology and Biochemistry
- Role
- Role Term:
Text
- sponsor
- Origin Information
- Copyright Date
- 2025
- Physical Description
- Extent
- xi, 94 p.
- digitalOrigin
- born digital
- Note:
thesis
- Thesis (Ph. D.)--Brown University, 2025
- Genre (aat)
- theses
- Abstract
- Alzheimer’s Disease (AD) is an age-related neurological disorder, with pathological hallmarks including the accumulation extracellular amyloid plaques consisting of amyloid beta (Aβ), processed from amyloid precursor protein (APP), and intracellular neurofibrillary tangles comprised of phospho-tau. These features are proceeded and precipitated by a wide range of intra- and inter-cellular functions, with derailed neuroinflammation being among the earliest manifestations in human brains. Of note, Chitinase-3-like protein 1 (CHI3L1, or YKL-40), an inflammatory protein mainly secreted by reactive astrocytes in the brain, has been documented to be a powerful AD biomarker, and its cerebrospinal fluid (CSF) level has recently been reported to be potentially the first disease indicator. However, how it functions in the brain and influences neuroinflammation and AD pathogenesis remains to be elucidated. In contrast, in peripheral tissues such as in the pulmonary system, CHI3L1 has been well characterized as an immune signaling molecule that controls many aspects of inflammatory processes via specific cell surface receptors and downstream signaling pathways. As such, I hypothesized that CHI3L1, secreted by reactivated astrocytes, functions as an inflammatory signaling molecule to mediate the neuroinflammatory responses in a cell type–specific manner and that such signaling function can derail and lead to neurodegeneration and relevant AD features. To define a role whereby CHI3L1 regulates glia-derived neuroinflammatory response and the resultant neurodegeneration, I utilized neurons, astrocytes, and microglia induced from human pluripotent stem cells. In induced neurons (iNs), CHI3L1 induces widespread transcriptomic alterations, induces apoptosis, and significantly increases levels of AD-associated features. Knock down of the known CHI3L1 receptor RAGE on neurons reduced some features relevant to AD and neurotoxicity, implicating RAGE as a main neuronal CHI3L1 receptor. To determine how CHI3L1 modulates glial cells in the presence of neurons, I utilized induced astrocytes (iA) and induced microglia (iMGs) in co-cultures with iNs and found that CHI3L1 modulates aspects of glial reactivity and inflammation. Overall, here I reveal a novel role CHI3L1 plays in the brain, departing from being merely a biomarker for AD and neuroinflammation.
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01036436")
- Topic
- Neurons
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00806532")
- Topic
- Alzheimer's disease
- Subject
- Topic
- Neurodegeneration
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01132975")
- Topic
- Stem cells
- Subject
- Topic
- neuroinflammation
- Language
- Language Term (ISO639-2B)
- English
- Record Information
- Record Content Source (marcorg)
- RPB
- Record Creation Date
(encoding="iso8601")
- 20251201